Delivering proteins and gene therapy vectors to widespread central nervous system (CNS) areas has to date been complicated by the barriers that exist between the bloodstream and the brain and spinal cord (Hammarlund-Udenaes et al. 2014). By “widespread,” we mean that the drug or pharmaceutical is delivered throughout the brain and spinal cord and achieves more global delivery to the CNS.
Many of the primary central sites of administration that bypass these barriers remain viable options in clinical trials because they offer the potential of targeted CNS drug delivery and yield high brain and CSF levels with low systemic exposure. Delivering drugs into the cerebrospinal fluid (CSF) in the hope that they may be efficiently transported into adjacent brain and spinal cord tissue has long been among the most promising of these approaches because of its clinical practicability compared to more invasive intraparenchymal injections or direct brain infusion (convection-enhanced delivery) (Calias et al. 2014).
The relevant anatomy and specific compartments containing the CSF are shown in FIG. 1 and have been described extensively (Thorne. 2014; Dayson & Segal. 1996). Briefly, the brain and spinal cord are immersed in CSF, which helps to suspend the brain and avoid its distortion due to a buoyancy force that balances the downward force due to gravity (Thorne. 2014). The CNS and CSF are together encased within the meninges (the dura mater, arachnoid and the pia mater) which provide additional stability; the dura mater is anchored to the skull while the arachnoid, which forms the leptomeninges with the pia, is adherent to the dura mater. Leptomeningeal arteries and veins run within the subarachnoid space surrounded by CSF. The CSF occupies several cavities or chambers within the brain (the ventricular system) as well as a larger volume filling the subarachnoid space that surrounds the brain and spinal cord.
The human brain contains four ventricles (FIG. 1A-D): two large, c-shaped lateral ventricles, a single third ventricle between the thalamus and hypothalamus of each hemisphere, and a single tent-shaped fourth ventricle located between the cerebellum, pons and medulla. CSF is actively secreted by the choroid plexuses of the lateral, third and fourth ventricles (FIG. 1C) such that there is a brisk flow of CSF within the system. CSF flows from the lateral ventricles to the third ventricle via two interventricular foramina, then from the third ventricle to the fourth ventricle via the cerebral aqueduct, and, finally, exits into several cisterns and the subarachnoid space via three apertures, one located medially and two located laterally in the fourth ventricle (FIG. 1D). CSF is ultimately reabsorbed back into the blood supply through arachnoid projections into the venous sinuses and also along cranial and spinal nerve roots to extracranial lymphatics. Additional CSF outflow may also occur along the perivascular sheaths of major blood vessels. In adult human beings, roughly 15% of the total CSF volume is present within the ventricular system, with the remainder located within the fluid-filled cisterns and subarachnoid spaces outside of the brain and spinal cord.
There are three principal sites of infusion into the CSF compartments that are typically used: intracerebroventricular (into one or both of the brain's lateral ventricles or into the third or fourth ventricle), cisternal intrathecal (into the cisterna magna fluid space located beneath the cerebellum), and lumbar intrathecal (into the lumbar subarachnoid fluid space located below the conus medullaris termination of the spinal cord) (FIG. 2) (Thorne & Frey. 2001). ICV administration provides a strategy that can potentially deliver a variety of agents to wide areas of the CNS due to the circulation of CSF within the ventricular and extraventricular compartments. Similarly, intrathecal administration approaches also may potentially deliver drugs to widespread areas of the CNS; although anatomically the intrathecal routes accomplish somewhat less contact with the interior surfaces of the brain (i.e. the brain-ventricle interfaces) than with the intracerebroventricular routes, the intrathecal routes are less invasive and will not result in damage to parenchymal tissue if cannula placement and drug administration are performed properly
However, decades of work have suggested that a severe diffusion limitation limits the transport of many macromolecules to only the most superficial regions of the brain and spinal cord when administered into the CSF (reviewed in Wolak & Thorne. 2013). Indeed, the resulting concentration gradients across the brain-CSF interface from diffusion are so steep that the levels of an infused 150 kDa antibody are expected to drop many million-fold just a few millimeters deep into the brain (See FIG. 3) (Wolak et al. 2015).
Needed in the art of drug delivery is an improved method of delivery to the CNS.